A once-weekly injection vs. a once-daily pill — both from Eli Lilly, both investigational. Which approach will matter more for patients?
Retatrutide and orforglipron are both investigational obesity drugs from Eli Lilly, but they represent fundamentally different strategic bets. Retatrutide pushes the boundaries of how much weight can be lost through a multi-receptor injectable approach. Orforglipron asks a different question: what if you could deliver meaningful GLP-1 benefits in a pill you take once a day, with no injections and no food restrictions?
These aren't really competing drugs — they're designed for different patients with different priorities. But understanding the trade-offs is important for anyone following this space.
Once-weekly subcutaneous injection. Triple agonist. Maximum metabolic impact. For patients who need the most aggressive weight loss intervention available.
Once-daily oral tablet. GLP-1 agonist only. No injection, no food/water restrictions. For patients who want effective treatment with maximum convenience.
Orforglipron is a small-molecule, non-peptide GLP-1 receptor agonist. Unlike injectable GLP-1 drugs (which are peptide-based and would be destroyed by stomach acid if swallowed), orforglipron's chemical structure allows it to survive oral ingestion and be absorbed through the gut. This is a significant pharmaceutical achievement — truly effective oral GLP-1 agonism has been the holy grail of metabolic medicine for years.
Existing oral semaglutide (Rybelsus) requires elaborate dosing protocols — it must be taken on an empty stomach with a small amount of water and the patient must wait 30 minutes before eating or drinking anything else. Orforglipron has no such requirements — it can be taken at any time regardless of food, dramatically improving the real-world usability.
| Category | Orforglipron | Retatrutide |
|---|---|---|
| Drug Type | Small molecule (non-peptide) | Peptide-based |
| Administration | Once-daily oral tablet | Once-weekly injection |
| Receptor Targets | GLP-1 only | GLP-1 + GIP + Glucagon |
| Food Restrictions | None | N/A (injectable) |
| Avg. Weight Loss (Phase 2) | ~14–15% | ~24% |
| FDA Status | ✗ Not approved — Phase 3 | ✗ Not approved — Phase 3 |
| Needle Phobia Friendly | ✓ Yes | ✗ No |
| Refrigeration Required | Likely no | Likely yes |
| Access in Low-Income Countries | Higher potential (pill format, stable) | Lower (injectable, cold chain) |
| Energy Expenditure Increase | No | Yes (glucagon pathway) |
| Liver Fat Reduction | Indirect (via weight loss) | Direct + indirect |
Phase 2 data shows a meaningful difference in weight loss between the two drugs. Orforglipron produced approximately 14–15% weight loss — very competitive with injectable semaglutide (Wegovy) — while retatrutide reached ~24% at its highest dose. That roughly 9–10 percentage point gap is clinically significant, potentially representing the difference between meaningful weight loss and transformative weight loss for a given patient.
However, it is important to note that orforglipron's weight loss is remarkably good for an oral pill. The convenience premium of not injecting yourself weekly is real for many patients, and if orforglipron can deliver Wegovy-level results in tablet form, the addressable patient population expands enormously — particularly among needle-averse patients and in markets where cold-chain injectable distribution is challenging.
Global health angle: Orforglipron's oral format and likely room-temperature stability could make GLP-1 therapy accessible in lower-income countries and rural settings where injectable drug distribution is logistically difficult. This is one reason Eli Lilly — and global health organisations — are watching orforglipron's development closely.
Have needle phobia or significant anxiety around injections. Want a simpler, more discreet treatment with no sharps disposal. Need a drug that can be stored at room temperature. Are seeking Wegovy-level weight loss without the injection burden. Live in areas with limited healthcare infrastructure for injectable drugs.
Need the maximum possible weight loss — those with severe obesity or seeking to avoid bariatric surgery. Have significant liver fat accumulation or diagnosed MASH. Have not responded adequately to GLP-1-only approaches. Are comfortable with weekly injections in exchange for superior metabolic outcomes.
Interested in learning more about orforglipron specifically? Visit Orforglipron-RX.com for dedicated coverage of Eli Lilly's investigational oral GLP-1 pill — including trial data, mechanism, and availability updates.